Comparison of Chimeric and Non-Chimeric Tolerance Using Posttransplant Total Lymphoid Irradiation

Abstract

Chimeric tolerance is more robust than non-chimeric tolerance in the model of posttransplant TLI, ATG, and donor cell infusion, and is associated with less chronic rejection.

Immune Tolerance to Combined Organ and Bone Marrow Transplants After Fractionated Lymphoid Irradiation Involves Regulatory NK T Cells and Clonal Deletion

“…This regimen has been used successfully to induce tolerance to vascularized heart allografts in rats and to kidney allografts in humans (7,13,14). Unexpectedly, the removal of the anti-T cell Abs from the regimen in the current study resulted in uniform heart graft rejection with uniform mixed chimerism.…”

“…This posttransplant-conditioning regimen consisting of total lymphoid irradiation (TLI) 3 and anti-thymocyte globulin has been previously shown to induce mixed chimerism and tolerance to vascularized heart grafts in completely MHCmismatched rats (13,14). A key advantage of the posttransplant regimen is that it can be applied to human cadaver organ transplantation.…”

“…To achieve long-term cardiac tissue allograft acceptance and mixed chimerism using BALB/c (H-2 d ) host and C57BL/6 (H-2 b ) donor mice, we conditioned hosts with a nonmyeloblative posttransplantation regimen of fractionated irradiation of the spleen, lymph nodes, and thymus with marrow shielding (TLI), depletive anti-T cell Abs, and an infusion of donor bone marrow cells that had been reported to tolerize MHC-mismatched rats (13,14). Host mice received neonatal donor heart allografts transplanted to the ear pinnae on day 0, 5 doses of ATS i.p.…”

Radiotherapy and Immunity – A Mini Review

“…Conditioning regimens used to achieve mixed chimerism and tolerance include lethal and sublethal total body irradiation (TBI) with or without thymic irradiation and anti-T cell antibodies (Ildstad & Sachs 1984;Kawai et al, 2002;Stykes 2001), www.intechopen.com TLI with and without anti-T cell antibodies (Slavin et al, 1976;Slavin et al, 1978;Slavin et al, 1977;Scandling et al, 2008 ;Hayamizu et al, 1999;Lan et al, 2000;Higuchi et al, 2002), costimulatory blockade with or without rapamycin therapy or cytoreduction (Wekerle et al, 2000;Durhan et al, 2000;Lambert et al, 2002;Graca et al, 2006), injection of naturally occurring CD4+CD25+ Treg (nTreg) cells combined with radiation cytoreduction (Golshayn et al, 2007;Wood & Sakaguchi, 2003), and chemical cytoreduction combined with thymic irradiation, and anti-T cell antibodies (Fudaba et al, 2006;Kawai et al 2008,). Although central and peripheral clonal deletion in chimeras can explain the lack of reactivity of host immune cells to donor alloantigens (Stikes 2001;Wekerle et al, 1998), host regulatory T cells that remain after cytoreduction or that are injected after cytoreduction can also play an important role in the engraftment of the donor organ and hematopoietic cells (Higushi 2002, Golshayn et al, 2007Wood & Sakaguchi 2003).…”

“…This lymphodepletive-conditioning regimen facilitated tolerance by altering the balance of host T cell subsets to markedly favor the NKT cells and Tregs over alloreactive host naïve (CD62LhiCD44lo) T cells. Therefore, the changes in the balance of regulatory and naïve T cell subsets and their contributions to graft acceptance or rejection using a TLI and ATS conditioning regimen is the responsible to induce mixed chimerism and tolerance after combined heart and bone marrow transplantation (Hayamizu et al, 1999;Lan et al, 2000;Higuchi et al, 2002). It was demonstrated that one day after the completion of TLI and ATS conditioning (time point of donor bone marrow infusion) there was a marked increase in the ratio of CD4+ CD25+Foxp3+ Treg cells and NKT cells to naïve conventional T cells.…”